Project Summary Aging of breast tissue microenvironment has reported to form a fertile soil facilitating tumor progression. As tissue hemostasis evolves over the course of aging, developing models that enable the exploration of tumor progression in aging niche is important for understanding the disease, identifying crucial pathways, and finding control points that could be amenable to therapeutic intervention. Systematic inquiry of the aged breast tissue environment has been challenging and cost prohibitive, due to 1) lack of aged NORMAL breast tissue (an ideal control) for tissue microenvironment analysis and 2) the logistic barrier of lengthy aging process when using experimental mouse models. A fully characterized, tissue engineered breast model that faithfully recapitulates breast cancer development in an aging-mimicking tissue would be a novel platform for studying breast cancer progression, and would bring a new perspective to breast cancer research. Using a microfabricated tissue engineered model, we can explore what constitutes a permissive aging stromal environment by modulating variables such as matrix stiffness, matrix components, stromal cell density and organization, etc. The central goals of the proposed effort are to establish an Aging-mimicking Breast Tissue engineered (ABTe) that will be used to characterize the factors that contribute to the permissive environment in aging tissues, including the physical, chemical, and cellular cues, and to investigate whether therapeutic modulation can affect tumor progression in aging microenvironment. Specifically we aim to 1) Characterize biophysical properties and biochemical composition of extracellular matrices (ECM) of aged breast tissue; and 2) Build ABTe system and model ECM heterogeneity by tuning aging-related ECM factors including ECM stiffness, ECM composition, and stromal adipocytes spatial distribution, and then 3) test the clinical relevance and power of the developed ABTe by running chemoprevention trails for prevention of transition from Ductal Carcinoma In Situ (DCIS) to Invasive Ductal Carcinoma (IDC). To achieve these goals, we will combine our expertise of tissue engineering and breast cancer research. Once fully implemented and functionally validated, we expect our state-of-the-art tissue engineered ABTe cancer model to serve as the next-generation research platform for both basic and translational cancer research and high-throughput drug discovery. The tissue engineered ABTe will greatly facilitate research efforts in important, while traditionally less accessible, areas of cancer research and beyond.